PROJECT SUMMARY/ABSTRACT Rett syndrome (RTT) is a severe neurodevelopmental disorder causing progressive loss of motor and cognitive functions, impaired social interactions, anxiety, and seizures in young girls. Mutations in the gene encoding MeCP2 (methyl-CpG binding protein 2) are the cause of RTT. It has been hypothesized that defects of neuronal circuit development and function are responsible for neurological symptoms of RTT. The majority of RTT patients have recurrent seizures, suggesting that hyperexcitation of the neocortex is a common feature of RTT. Consistent with clinical data, MeCP2-deficient mice also show cortical hyperexcitation and seizures. Besides epilepsy, hyperexcitation of the neocortex may have major roles in cognitive and behavioral defects of RTT. Reducing cortical hyperexcitation is a potential treatment strategy for RTT. However, mechanisms underlying cortical hyperexcitation in RTT are poorly understood. This application will test the hypothesis that loss of MeCP2 in excitatory neurons in the cortex causes hyperexcitation by downregulating GABAergic transmission in the cortex. In testing this hypothesis, we take advantage of genetic manipulation in the mouse, electrophysiology, and our expertise in physiology and development of cortical neurons. The two specific aims are: 1) to determine the role of MeCP2 in regulating inhibitory neurotransmission in the cortex; and 2) to investigate of the effects of MeCP2 deficiency on cortical excitability and seizures.